Methods for the asymmetric construction of quaternary carbon atoms are rare. This particularly applies for the synthesis of tertiary alcohols, which still represents a challenge for a synthetic organic chemist. The most direct approach for the asymmetric preparation of tertiary alcohols consists in a stereselective addition of an organometallic reagent to a ketone. However, reagent controlled and catalyzed methods are limited to a few examples (see: Ramon, D. J.; Yus, M. Angew. Chem. Int. Ed. 2004, 43, 284-287). Thus, there is a need for methods for the preparation of chiral tertiary alcohols.
A tertiary alcohol of particular interest is compound of formula (II), which is the key intermediate in the production of the drug escitalopram (I), which is a well-established antidepressant. It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities.

Escitalopram was first disclosed in EP 347066 by H. Lundbeck A/S. In this patent publication the substance is claimed and two methods for the preparation based on a separation of the R- and S-enantiomer of a synthesis intermediate are given followed by a conversion of enantiomerically pure diol (II) or labile esters thereof to escitalopram (I).
The first method includes a transformation of racemic 4-[4-dimethylamino-1-(4-fluoro-phenyl)-1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile (formula (II)) into the corresponding two diastereomeric esters (by using a chiral acid chloride), which can be separated by chromatography on an achiral stationary phase or fractional crystallization. The ester with the desired stereochemistry is converted into escitalopram by a base promoted ring closure reaction. The racemic diol of formula (II) and its use in the synthesis of citalopram have been disclosed in U.S. Pat. No. 4,650,884.
The second method described in EP 347066 is based on a separation of the racemic diol of formula (II) by a classical resolution using (+)-di-O′,O′-toluoyltartaric acid as resolving agent. The yield for this resolution according to EP 347066 is 55% (27.5% calculated on racemic diol (II)). The enantiomerically pure diol is submitted to a subsequent dehydrative ring closure reaction (MsCl, Et3N) to give escitalopram.
In WO 03/006449 the separation of the enantiomers of diol (II) by preparative chromatography on a chiral stationary phase is disclosed. Ee's (enantiomeric excess) of more than 99% and yields of more than 95% (47.5% calculated on racemic diol (II)) can be obtained by this separation method. The large scale chromatography is technically realized by using SMB technology (SMB=simulated moving bed) on a carbohydrate based stationary phase. Conversion of enantiomerically pure diol (II) to escitalopram is performed according to EP 347066.
In WO04/014821 a fourth approach is disclosed, which relies on the use of enzymes (esterases and lipases) for the separation of the racemic diol of formula (II). A kinetic enzymatic acylation or deacylation of racemic diol (II) or esters of racemic diol (II), respectively, results in a mixture containing preferentially one of the enantiomers as diol of formula (II) and the second enantiomer as ester of diol (II). After separation the ring closure can be performed as described above.
All of the four described approaches to enantiopure escitalopram start from the racemic diol of formula (II). The theoretical overall yield of escitalopram obtained by any of these processes is limited to 50% based on racemic diol (II).
Though highly desirable an asymmetric synthesis to an enantiomerically enriched or pure diol of formula (II), which is not based on a separation of racemic diol (II), has not been reported so far. Such a synthesis would significantly increase the overall yield to escitalopram.
It has now been found that boric or boronic acid derivatives are useful bridging elements for the attachment of a chiral group to a compound containing a carbonyl group to be alkylated. The borates and boronates are thus useful in a process for the asymmetric alkylation of a carbonyl group in a compound containing a carbonyl group and a functional group (in the following referred to as “anchor” group) capable of reacting with a boric or boronic acid derivative. The asymmetric alkylation can be carried out by admixing the compound containing a carbonyl group to be alkylated and the anchor group capable of reacting with a boric or boronic acid derivative with a boric or boronic acid derivative, adding a chiral alcohol, and adding an organometallic compound. After the alkylation reaction, the borate and boronate can be easily removed by hydrolysis.
By using the process of the invention, the desired S-enantiomer of diol (II) (or the corresponding R-enantiomer) can be prepared in high yield. Thus, escitalopram can be synthesized without the need for separation of racemic diol (II).